Abstract 30: Intermittent treatment with the PARP inhibitor olaparib delays tumor development in BRCA1-deficient mice

Women with inherited BRCA gene mutations are at extremely high risk for developing breast cancer. Although these high risk patients are ideal candidates for an effective chemoprevention regimen, “watchful waiting” or bilateral prophylactic mastectomy are the only currently available options. BRCA proteins are required for repairing double strand DNA breaks through homologous recombination. In BRCA-deficient cells, DNA is repaired by base excision repair, which requires a PARP protein. PARP inhibitors can selectively induce apoptosis in BRCA-deficient cells, without affecting normal cells, by blocking the only DNA repair pathway available to these cells. Various PARP inhibitors are being tested in the clinic in women with BRCA mutations, and if effective, these drugs might also be useful for chemoprevention. When fed continuously in diet, the PARP inhibitor olaparib (200 mg/kg diet) significantly delayed tumor development by 6.5 weeks in the aggressive Brca1Co/Co;MMTV-Cre;p53+/- mouse model. An intermittent schedule was then tested; olaparib was given for 2 week cycles in order to induce apoptosis in premalignant cells followed by 4 week rest periods in an attempt to reduce drug toxicity. Intermittent therapy with olaparib was nearly as effective as the continuous feeding protocol and increased the age of initial tumor onset to 35.6 ± 1.0 wks compared to 29.9 ± 1.1 wks in the control group (P Supported by Susan G. Komen for the Cure and the Breast Cancer Research Foundation Citation Format: Karen T. Liby, Ciric To. Intermittent treatment with the PARP inhibitor olaparib delays tumor development in BRCA1-deficient mice. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 30. doi:10.1158/1538-7445.CANSUSC14-30